Genetic Analysis of the Induction and Morphogenesis of the Inner Ear

内耳诱导和形态发生的遗传分析

• 批准号: 7989984
• 负责人: Katherine Shim
• 金额: $ 36.78万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989984
• 关键词: Accounting; Address; Brain; Cells; Chickens; Congenital Abnormality; Data; Development; Ectoderm; Embryo; Embryonic Development; Embryonic Induction; Epithelium; Equilibrium; Event; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Family; Genes; Genetic; Goals; Hair Cells; Hearing; Hearing problem; Human; In Vitro; Individual; Labyrinth; Lead; Mechanics; Membrane; Mesenchyme; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Nature; Neurons; Organ; Organ Size; Organism; Otic Placodes; Pathway interactions; Play; Process; Proteins; Pseudostratified Epithelium; Receptor Protein-Tyrosine Kinases; Regenerative Medicine; Regulation; Role; Sensory; Side; Signal Pathway; Signal Transduction; Stem cells; Supporting Cell; Testing; Tissues; Zebrafish; base; cell injury; cell type; equilibration disorder; gene function; genetic analysis; hindbrain; induced pluripotent stem cell; malformation; member; mutant; notch protein; novel; pressure; progenitor; public health relevance; sound

DESCRIPTION (provided by applicant): Development of the inner ear begins when two regions of ectoderm on either side of the embryonic hindbrain form thickened patches of epithelium called the otic placodes. All of the cell types that compose the membranous inner ear, including the mechanosensory hair cells and the neurons that innervate them, are descendents of cells in the otic placode. Consequently, any perturbations in formation of the otic placode can have severe consequences on the formation and function of the inner ear. Furthermore, it is estimated that up to 39% of cases of congenital hearing and balance disorders are associated with malformation of the inner ear. The long-term goal of this project is to understand the molecular pathways required for induction of the otic placode, which should enhance our understanding of those congenital hearing and balance disorders associated with inner ear malformation. Here we propose a genetic approach to elucidate the role of the Sprouty family of antagonists of receptor tyrosine kinase signaling, including Fibroblast Growth Factor (FGF) signaling, in otic placode induction. The specific aims of this proposal are: Aim 1) To analyze the redundant functions of the Spry1 and Spry2 genes during otic placode induction and to test the hypothesis that Spry1 and Spry2 function redundantly to limit the range of FGF signaling during induction of the otic placode. Aim 2) To test the hypothesis that Spry1 and Spry2 function redundantly at an early step in otic placode induction, and that other signaling pathways that contribute to otic placode induction will be misregulated in the absence of both Spry1 and Spry2 gene function. Aim 3) To determine the gene-sufficiency of the individual Spry1 and Spry2 genes during otic placode induction and to test the hypothesis that the tissue-specific expression of Spry1 and Spry2 is critical for proper induction of the otic placode. PUBLIC HEALTH RELEVANCE: We propose a genetic approach to explore the signals required for induction of the embryonic progenitor cells that give rise to the inner ear. This study should enhance our understanding of congenital hearing and balance disorders resulting from malformation of the inner ear, such as Michel- and Mondini-type aplasia, and should inform attempts to generate progenitor cells of the inner ear for regenerative medicine.

描述（由申请人提供）：内耳的发展开始时，当胚胎后脑的两侧两个外胚层区域形成了称为Otot lopodes的上皮的增厚斑块时。组成膜内耳朵的所有细胞类型，包括机械感觉毛细胞和神经元的神经元，都是细胞中细胞的后代。因此，任何形成耳片的扰动都可能对内耳的形成和功能产生严重的后果。此外，据估计，先天性听力和平衡障碍的病例中，多达39％的内耳畸形有关。该项目的长期目标是了解诱导OTOCEPODE所需的分子途径，这应该增强我们对那些先天性听力和与内耳畸形相关的疾病的理解。在这里，我们提出了一种遗传方法，以阐明受体酪氨酸激酶信号传导的发芽家族的作用，包括成纤维细胞生长因子（FGF）信号传导，在动态placode诱导中。该提案的具体目的是：目标1）在耳模诱导过程中分析SPRY1和SPRY2基因的冗余功能，并测试SPRY1和SPRY2功能的假设，以限制OTOT placode诱导过程中FGF信号传导的范围。目的2）测试以下假设：SPRY1和SPRY2在OIT placode诱导的早期步骤中有效地功能，并且在没有SPRY1和SPRY2基因功能的情况下，其他有助于耳置诱导的信号传导途径将被误导。目的3）确定在耳模式诱导过程中单个SPRY1和SPRY2基因的基因纯净，并测试假设SPRY1和SPRY2的组织特异性表达对于正确诱导OTOT plapode至关重要。 公共卫生相关性：我们提出了一种遗传方法，以探索诱导产生内耳的胚胎祖细胞所需的信号。这项研究应增强我们对先天耳朵畸形所导致的先天性听力和平衡疾病的理解，例如米歇尔（Michel-和Mondini-type aplasia），并应告知试图产生内耳的祖细胞以生成再生医学的祖细胞。